Genetic Abnormalities – ALK

An estimated 3-5% of lung tumors have mutations on the ALK gene, which stands for Anaplastic Lymphoma Kinase. ALK mutations are more common in light smokers (defined as less than 10 pack years*) and/or never-smokers (patients are considered “never smokers” if they have smoked less than 100 cigarettes in their lifetime). These mutations are also associated with younger patient age and adenocarcinomas.1,2

Role of ALK

ALK is one of several receptor tyrosine kinases (RTKs). RTKs are cell-surface receptors that partner with ligands, proteins which activate the receptor to cause a specific action in the cell.3

In its normal capacity, the ALK gene provides instructions for a protein (anaplastic lymphoma kinase) that plays an important role in cell growth, division, and maturation. Damage to the genes causes normal cells to change and become cancer cells. When there is a mutation to ALK gene, the malignant (cancerous) cells are activated to grow and multiply.1,2

Targeted Treatment for ALK

In the majority of cases, the presence of an ALK mutation on tumor cells generally occurs on its own without other genetic mutations, including EGFR mutations, KRAS, and others. Tumors with ALK mutations can respond to targeted therapy, making testing for these mutations an important part for tailoring treatment to a specific patient.1,5

Drugs that target the abnormal ALK protein are known as ALK tyrosine kinase inhibitors (TKIs). Although they may be used after chemotherapy has stopped working, ALK TKIs are often used instead of chemotherapy as a patient’s initial treatment. There are currently three ALK TKIs that are approved by the U.S. Food and Drug Administration (FDA). Several additional ALK TKIs are currently in clinical trials.4,5

Xalkori (crizotinib) – In an initial clinical trial, patients with ALK mutation whose lung cancer had progressed despite a prior line of treatment showed response rates of 50-60% when treated with Xalkori. Researchers have conducted analyses of patients across two trials to estimate the benefit of Xalkori therapy. Patients who were treated with Xalkori as a second-line therapy (after a prior treatment failed to work) had a 1-year overall survival rate of 70% and a 2-year overall survival rate of 55%.1,4,5

Zykadia (ceritinib) – Zykadia was approved by the FDA in April 2014 after demonstrating effectiveness in clinical trials among patients who were positive for ALK mutation. Clinical trial results showed that Zykadia was highly effective in patients, including those for whom treatment with Xalkori didn’t work. In one trial, ALK-positive patients had a 60% response rate when treated with Zykadia.1,4,5

Alecensa (alectinib) – The FDA gave an accelerated approval for Alecensa in December 2015 for patients with ALK-positive tumors whose disease has progressed despite treatment with Xalkori, as well as patients who are intolerant to Xalkori.1,4,5 In November of 2017, Alecensa was approved by the FDA as a first-line treatment option for NSCLC patients with ALK gene mutation.6

Some patients have developed resistance (the drug no longer works to treat the cancer) to TKI therapy, in particular, to Xalkori. Acquired resistance is defined as lung cancer that has progressed while still receiving therapy after an initial response. The mechanisms of how acquired resistance occurs to Xalkori are not completely understood at this time. Researchers are studying whether specific mutations on the ALK gene might be responsible for the resistance, as well as novel (new) therapeutic strategies to overcome or prevent the development of acquired resistance.1

*Pack years is a term used to help quantify the equivalent of how many years a patient has smoked. It is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked. For example, smoking one pack per day for one year equals 1 pack year, whereas smoking two packs per day for two years equals 4 pack years.

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